The absence of reliable biomarkers for intrathecal inflammation is a critical impediment to broad therapeutic progress in neuroimmunology. This notion is exemplified by augmented therapeutic developments in relapsing-remitting multiple sclerosis (RRMS) driven by the recognition that contrast-enhancing lesions (CELs) on brain magnetic resonance imaging (MRI) reflect perivascular inflammation (Sormani and Bruzzi, Lancet Neurol 12(7):669-676, 2013; Filippi et al., Lancet Neurol 11:349-360, 2012). Unfortunately, clinical success of CELs led to a false generalization that CELs are always associated with inflammation or represent all inflammatory activity. Such assumptions can lead to the administration of immunomodulatory agents to patients whose primary pathology is hypoxia or malignancy, or to the simplified (and possibly incorrect) conclusion that the immune system no longer plays a role in progressive multiple sclerosis (MS).
The evaluation of cerebrospinal fluid (CSF) has been paradoxically discouraged, partly by an erroneous perception that the lumbar puncture is dangerous, but most importantly, by the limited clinical value of available CSF biomarkers (Stangel et al., Nat Rev Neurol 9(5):267-276, 2013). When determining if patients have an immune-mediated central nervous system (CNS) disease or when recommending options for patients with neuroimmunological disorders who are unresponsive to applied treatment, IgG index, oligoclonal bands (OCBs), or CSF pleiocytosis provide unsatisfactory sensitivity/specificity ratios (Link et al., J Neuroimmunol 180:17-28, 2006). The customary solution is a brain biopsy or a blind trial of immunomodulatory agents. Unfortunately, both approaches expose patients to substantial risks and may still lead to unsatisfactory outcomes. Indeed, brain biopsies in neuroimmunological disorders are frequently “non-diagnostic,” either due to sampling error, limited diversity of immunohistochemical stains, or the development of “non-specific” inflammation by the time such a radical diagnostic step is considered.
Hence, there remains a great need for direct biomarkers of intrathecal inflammation, including biomarkers of MS, ideally those that provide information about the phenotype of the inflammatory process (Bielekova and Martin, Brain 127:1463-1478, 2004).